In situ forming hemostatic foam implants

ABSTRACT

Systems and methods related to polymer foams are generally described. Some embodiments relate to compositions and methods for the preparation of polymer foams, and methods for using the polymer foams. The polymer foams can be applied to a body cavity and placed in contact with, for example, tissue, injured tissue, internal organs, etc. In some embodiments, the polymer foams can be formed within a body cavity (i.e., in situ foam formation). In addition, the foamed polymers may be capable of exerting a pressure on an internal surface of a body cavity and preventing or limiting movement of a bodily fluid (e.g., blood, etc.).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application continuation of U.S. patent application Ser. No.17/548,844, filed Dec. 13, 2021, which is a divisional application ofU.S. patent application Ser. No. 16/376,087, filed Apr. 5, 2019, whichis a continuation of U.S. patent application Ser. No. 14/928,857, filedOct. 30, 2015, which is a divisional of U.S. patent application Ser. No.13/209,020, filed Aug. 12, 2011, which is a continuation-in-part of U.S.patent application Ser. No. 12/862,362, filed Aug. 24, 2010, whichclaims priority to U.S. Provisional Patent Application No. 61/368,095,filed Jul. 27, 2010 and U.S. Provisional Patent Application No.61/236,314, filed Aug. 24, 2009, which are incorporated by referenceherein for all purposes.

FIELD OF INVENTION

Systems and methods relating to polymer foams are generally described.

BACKGROUND

Early stabilization of body fluid loss can be important in the treatmentof wounds. For example, many injuries are treatable if effectivehemorrhage control and operative surgical intervention are undertakenrapidly. However, in many situations, immediate access to surgical careis not available. Internal wounds may be particularly difficult to treatin such situations, as traditional treatment techniques (e.g.,application of pressure to stop bleeding, etc.) are difficult toimplement with such wounds.

The use of polymers in the treatment of wounds is well known in the art.However, previous materials and methods for treating wounds withpolymers have suffered from a variety of drawbacks. For example, manypolymers irritate skin and/or internal tissues, or are not sufficientlybiodegradable to be suitable for use inside a body cavity. Moreover,many polymers also lack suitable mechanical properties to be usefulinside the body; polymers that are too stiff may lead to discomfort orfurther injury, while polymers that are too soft may fail to provideadequate support for internal tissues.

Finally, polymers can be difficult to place within a body cavity.

SUMMARY OF THE INVENTION

Systems and methods relating to polymer foams are provided. The subjectmatter of the present invention involves, in some cases, interrelatedproducts, alternative solutions to a particular problem, and/or aplurality of different uses of one or more systems and/or articles.

In one aspect, the present invention comprises a method comprising theintroduction of a flowable polymer formulation into a body cavity,foaming the polymer formulation within the body cavity to produce anelastomeric polymer foam, and preventing or limiting bleeding within thebody cavity, relative to an amount of bleeding that would occur underessentially identical conditions in the absence of the elastomericpolymer foam.

In certain embodiments, the method comprises a method comprisingcross-linking a condensation polymer of a polyol and a polyacid within abody cavity, foaming the condensation polymer within the body cavity toproduce an elastomeric polymer foam, and preventing or limiting movementof a bodily fluid within the body cavity, relative to an amount ofmovement of bodily fluid that would occur under essentially identicalconditions in the absence of the elastomeric polymer foam.

In certain embodiments, the present invention comprises a methodcomprising the injection of a flowable polyol and polyisocyanate mixtureinto a body cavity, foaming the polymer formulation within the bodycavity to produce an elastomeric polymer foam, and preventing orlimiting bleeding within the body cavity, relative to an amount ofbleeding that would occur under essentially identical conditions in theabsence of the elastomeric polymer foam.

In another aspect, the present invention comprises a method of forming afoam within a body cavity by introducing a two part formulation into abody cavity, foaming the formulation, cross-linking the formulation, andpreventing or limiting movement of a bodily fluid within the bodycavity, relative to an amount of movement of a bodily fluid that wouldoccur under essentially identical conditions in the absence of the foam.In certain embodiments, the formulation and/or the foam can havephysical characteristics that are advantageous for preventing orlimiting the movement of a bodily fluid, including hydrophilicity,hydrophobicity, hygroscopy or miscibility with water, the degree ofexpansion of the foam, the density of the foam, the softness of thefoam, the viscosity of the formulation, and the kinetics of formformation from the formulation.

In another aspect, the present invention comprises a method comprisingplacing a polymer foam between two tissues to prevent tissue adhesion.

In other aspects, the invention includes foams, compositions,formulations, products, kits, and systems that are useful for performingthe methods described above.

The present invention offers advantages not previously known in the art.For example, the polymers of the invention can be deployed into a closedbody cavity without requiring specific knowledge of injury site(s) whilenonetheless creating conformal contact with actively bleeding injurieslocated throughout the cavity. Other advantages and novel features ofthe present invention will become apparent from the following detaileddescription of various non-limiting embodiments of the invention whenconsidered in conjunction with the accompanying figures.

In cases where the present specification and a document incorporated byreference include conflicting and/or inconsistent disclosure, thepresent specification shall control. If two or more documentsincorporated by reference include conflicting and/or inconsistentdisclosure with respect to each other, then the document having thelater effective date shall control.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the present invention will be described byway of example with reference to the accompanying figures, which areschematic and are not intended to be drawn to scale. In the figures,each identical or nearly identical component illustrated is typicallyrepresented by a single numeral. For purposes of clarity, not everycomponent is labeled in every figure, nor is every component of eachembodiment of the invention shown where illustration is not necessary toallow those of ordinary skill in the art to understand the invention. Inthe figures:

FIGS. 1A-1C include schematic illustrations of the formation of apolymer foam, according to one set of embodiments;

FIGS. 2A-2B include exemplary schematic illustrations of cross-linkingof polymers;

FIG. 3 includes a schematic illustration of cross-linking and gasgeneration, according to one set of embodiments; and

FIGS. 4A-4C include exemplary schematic illustrations of the formationof a polymer foam.

FIG. 5 includes expansion volumes of certain foams of the invention.

FIG. 6 includes water uptake values of certain foams of the invention.

FIG. 7 includes rise time and cream time values for certain formulationsof the invention.

FIG. 8 includes an exemplary schematic illustration of an in situapposition assay used to evaluate formulations and foams of theinvention.

FIG. 9 includes an exemplary photograph of a foam following testing inan in situ apposition assay.

FIG. 10 includes exemplary photographs of foams of the inventionfollowing testing in an vivo apposition assay.

FIG. 11 includes compression force values at 50% compression for certainfoams of the invention.

FIG. 12A-12C includes compression force values at 50% compression,intra-abdominal pressures, and peak airway pressures for certain foamsof the invention evaluated in the in vivo apposition assay.

FIG. 13 includes fluid resistivity measurements for certain foams of theinvention. FIG. 14 includes fluid uptake and pore size values forcertain foams of the invention.

FIG. 15 includes blood loss measurements for certain foams of theinvention evaluated in the in vivo apposition assay.

FIG. 16 includes blood loss measurements plotted against net appositionscores for certain foams of the invention evaluated in the in vivoapposition assay.

FIG. 17 includes a photograph of a foam of the invention evaluated inthe in vivo apposition assay having a projection.

FIG. 18 includes potential indications for foams of the inventionaccording to various foam functionalities.

FIG. 19A-19B includes a table of the transport scoring system for invivo studies (FIG. 19A) and a table showing the transport scores forvarious formulations of the disclosure (FIG. 19B).

FIG. 20A-20D includes four tables showing the characteristics ofmaterials with a high net apposition score (FIG. 20A), a low netapposition score (FIG. 20B), low blood loss (FIG. 20C), and high bloodloss (FIG. 20D). The grade V splenic injury creates four splenic piecesand six cut surfaces. Each was scored using the semi-quantitativetransport scoring system. Cumulative score and the number of edges witha score greater than two is shown in FIG. 20D.

FIG. 21 is a table showing examples of polyurethane foam compositionsformed by cross-linking polyols with isocyanates.

DETAILED DESCRIPTION

Systems and methods related to polymer foams are generally described.Some embodiments relate to compositions and methods for the preparationof polymer foams, and methods for using the polymer foams. The polymerfoams can be applied to a body cavity (including, but not limited to theabdominal, pelvic, and cardio thoracic cavities) and placed in contactwith, for example, tissue, injured tissue, internal organs, etc. In someembodiments, the polymer foams can be formed within a body cavity (i.e.,in situ foam formation). In addition, the foamed polymers may be capableof exerting a pressure on an internal surface of a body cavity andpreventing or limiting movement of a bodily fluid (e.g., blood, etc.).Foams of the invention can be used to treat incompressible hemorrhagefrom wound sites that are unknown or unable to be visualized withinpotentially tortuous body cavities. Certain compositions of theinvention can be deposited within a body cavity and reacted to formpolymer foams within or proximal to a wound site, which foams may applypressure to or limit fluid flow from the wound site. Alternatively,compositions of the invention can be deposited distal from a wound siteto create a foam that expands in volume to fill a body cavity, achievingclose apposition to a wound and thereby applying pressure thereto orlimiting the flow of fluids therefrom.

The polymer foams may possess attributes that make them particularlysuitable for use within the body. For example, in some embodiments, thepolymers used to form the foams described herein may be biocompatible.The polymers may also be biodegradable in some cases. In some instances,the polymers may be sufficiently elastic to allow for body movementwhile being sufficiently stiff to support body tissues. In someembodiments, the composition of the polymer may be adjusted so that itwets tissues effectively. Furthermore, pendant groups may be attachedthat allow for the targeted adhesion of polymer to tissues or injuredtissues. Functionalization of the polymer used to form the foam may alsolead to covalent bonding of the foam to a surface inside the bodycavity, which may aid, for example, in preventing dislocation of thefoam within the cavity.

The materials and methods described herein exhibit several advantagesrelative to traditional wound treatment methods. For example, someembodiments described herein allow for the delivery of polymer directlyto, and permeation throughout, a body cavity. The viscosity and wettingproperties of the polymers can be tailored such that the polymers areeasily injected into a wound cavity, forming, in some cases, a rapidlyexpanding elastomeric foam that fills the body cavity, coats one or moretissue surfaces, and/or cross-links within the body cavity. In addition,the polymers may comprise entities that allow for the degradation of thepolymer foam via an external stimulus such as UV radiation, heat, etc.The polymers and/or foams formed therefrom may also be capable ofinteracting with contrast agents, allowing for the visualization of abody cavity.

Additional advantages of the polymer foams described herein aredescribed in more detail below.

Polymer foams may be used in a variety of applications. In someembodiments, the polymer foams may be used to provide support to and/orstabilize bodily fluid loss from organs (e.g., the liver, spleen, etc.).Such use may be advantageous in treating organs or tissues that aredamaged, for example, in blunt trauma injuries. The polymer foams mayalso be used to fill a body cavity created by the loss of body tissue.As used herein, “body cavity” refers to any space located within a bodyincluding spaces within the external surface of the skin. It should benoted that body cavities may be, in some cases, exposed to the externalenvironment surrounding a body, such as, for example, in the case of anopen wound or surgical incision. In some embodiments, polymer foams maybe formed or located within an enclosed body cavity, for example, byplacing a polymer in the body cavity and closing an incision such thatthe polymer or polymer foam are not exposed to the external environment.While the embodiments described herein may find particularlyadvantageous use within body cavities, the use of the polymer foams arenot limited to body cavities, and may be used, for example, to treatburns and other external wounds.

Examples of polymer foams and methods associated therewith are nowprovided. In particular, systems and methods for foaming a polymer toform a polymer foam are now described in connection with one set ofembodiments. FIGS. 1A-1C include schematic illustrations of theformation of a polymer foam within a body cavity. As used herein, a“polymer foam” refers to an article comprising a plurality of cells(i.e. volumes) that are at least partially surrounded by a materialcomprising a polymer. The cells within the foam may be open or closed.The cells within the foam may be any suitable size. In some embodiments,the polymer foam may comprise at least 10 cells, at least 100 cells, atleast 1000 cells, at least 10,000 cells, or more.

FIG. 1 A includes body cavity 10 in which a polymer foam can be formed.In FIG. 1B, polymer material 12 is provided to cavity 10 via source 14.The polymer material can comprise a plurality of polymers which can be,for example, cross-linked to each other in the process of forming apolymer foam. In some embodiments, the polymer material comprises fluidpolymers in the substantial absence of a carrier fluid. In otherinstances, the plurality of polymers in the polymer material aresuspended in a carrier fluid (e.g., a liquid suspension medium, etc.).The term “polymer” is given its ordinary meaning in the art, and is usedto refer to a molecule that includes a plurality of monomers. In someembodiments, a polymer may comprise fewer than about 100, fewer thanabout 50, fewer than about 25, or fewer than about 10 monomer units. Insome embodiments, a polymer may comprise between about 2 and about 100,between about 2 and about 50, between about 2 and about 25, betweenabout 5 and about 50, or between about 5 and about 25 monomer units. Thepolymers within the polymer material can comprise a variety offunctional groups that allow the polymers to, for example, cross-link toeach other, attach to tissue or other material within the body cavity,interact with agents in the bloodstream of the subject (e.g., imagingagents, cross-linking agents, etc.), among other functionalities.

Source 14 may comprise any suitable source known to one of ordinaryskilled in the art. In some embodiments, source 14 comprises anysuitable container through which polymer material 12 may be passed. Forexample, in some embodiments, the source may comprise a syringe havingone or more barrels through which the polymer material is flowed. Insome embodiments, the source may comprise a container in which thepolymer material is under pressure, and the polymer material is releasedfrom the container upon depressurizing the container (e.g., as in anaerosol can). In such embodiments, the polymer material can be appliedas a spray, for example. The container may comprise several means forpressurizing known to those of ordinary skill in the art. For example,the container may be pressurized during the filling process in amanufacturing environment, or pressure may be generated immediatelyprior to use. In one embodiment, one or more pressure-generatingchemical reactions may occur within the container, with the userinitiating the reaction, waiting for pressure build-up and releasing thematerial. In another embodiment, pressure may be generated manually, viahand pump, crank, or rotary device. The container may also have anattachment that is introduced into the body that allows the material toflow into the cavity such as a Veress needle or nozzle or other meansknown to those of ordinary skill in the art. The openings on theintroducer tip can be multidirectional in order to distribute thepolymer in all directions within the cavity. That attachment orintroducer may be rigid, soft, straight, flexible or conformable to atortuous path. The introducer may have various tips for easy entry intothe abdominal cavity through the tough abdominal wall and muscles. Itmay also have a flexible or retractable tip that will protect organs,intestines, bowels from perforations. It may be shaped to be non-coringand atraumatic. A surface finish or coating such as PTFE or silicone maybe applied to part of or all of the introducer to make it lubricious andeasy to introduce into the body. Additionally, a surface finish orcoating can be applied to part or all of the introducer to make itremain in position once it is introduced. The surface finish or coatingcan be directional, allowing easy insertion but difficult removal.

In some embodiments, the polymers within the polymer material maycross-link within the body cavity. The term “cross-linking” is used torefer to the process whereby a pendant group on a first polymer chainmay react with a second polymer chain (e.g., a pendant group on thesecond polymer) or other molecule or molecules to form a covalent orionic bond joining the two polymers. Polymers that can undergocross-linking can comprise straight chains, branched chains having oneor more arms (i.e., multi-arm chains), or mixtures of these. In somecases, the polymer (branched and/or non-branched) may contain reactiveside chains and/or reactive terminal groups (i.e., groups at the end ofa polymer chain), and cross-linking may involve reactions between theside chains, between terminal groups, and/or between a side chain and aterminal group. For example, in FIG. 2A, polymers 20 and 22 arecross-linked, with bond 24 (which may comprise a single covalent bond ora plurality of covalent bonds between multiple atoms) between monomer 26and monomer 28. In addition, bond 30 is formed between non-terminalmonomer 32 and terminal monomer 34. In FIG. 2B, branched polymers 40 and42 are cross-linked, with bond 44 between monomer 46 and terminalmonomer 48, and bond 50 between monomers 52 and 54. In some instances,the polymer material may be substantially free of polymers that comprisereactive groups on terminal monomers. In other cases, the polymermaterial may comprise a substantial amount of polymers with reactivegroups on terminal monomers. In some embodiments (e.g., in some cases inwhich branched polymers are employed) a relatively large percentage ofthe cross-linking reactions (e.g., at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 99%, orsubstantially all of the cross-linking reactions) can occur betweenterminal reactive groups.

Cross-linking may commence via a variety of mechanisms. In someembodiments, polymer may cross-link once the polymer contacts moisture(e.g., water, blood, aqueous solutions, etc.), for example, within abody cavity. Cross-linking may be achieved via acrylate, methacrylate,vinyl, cinnamic acid, or acrylamide groups in some embodiments. Suchgroups may be cross-linked via the application of ultraviolet radiationand can be used in conjunction with an external foaming agent. In someinstances, a cross-linking initiator may be introduced into the subjectin which the body cavity is located (e.g., via the bloodstream, via aseparate container in the delivery system such that the initiator andthe polymer do not mix before delivery, etc.) to initiate cross-linkingof the polymer. For example, a free radical initiator, such as eosin or2, 2-dimethoxy-2-phenylacetophenone, can be used to initiatecross-linking of polymers bearing acrylate, methacrylate, or vinylgroups. Other examples of reactive groups on polymer chains that can bepaired to produce cross-linking include, but are not limited to,hydroxyls and isocyanates, amines and NHS-esters, thiols and maleimides,azides and alkynes (i.e. “click chemistry”), acid chlorides andalcohols, and in a preferred embodiment, isocyanates and polyols. It maybe desirable, in some embodiments, to keep these paired chemicalsseparate until they are introduced into the body cavity to preventunwanted cross-linking outside the body cavity. For example, the polymermay include azide functional groups, and alkynes can be introduced tothe body cavity from a container separate from the container used tointroduce the polymer. In some embodiments, these chemistries are alsoemployed in conjunction with an external foaming agent. As the polymermaterial cross-links, its viscosity may be increased. In some cases, thecross-linking proceeds until a substantially solid material (e.g., asolid elastomeric foam) is formed.

Referring back to the example in FIG. 1 , polymer material 12 (and/or across linked or partially cross-linked product of the polymer material)is foamed to form polymer foam 16, as illustrated in FIG. 1C. The foammay be formed, for example, by introducing a gas into the polymermaterial. Once the gas is supplied to the polymer, the gas may bedispersed within the polymer (e.g., as bubbles) to form the cells of thefoam. The dispersion of gas within the polymer may lead to expansion ofthe polymer such that it substantially fills the body cavity, as shownin FIG. 1C. In some cases, the foaming step may involve self-expansionof the polymer, for example, when gas is generated by a hydrolysisreaction or as a byproduct of a reaction between functional groups ondifferent polymer chains. Thus, cross-linking and foaming may take placesubstantially simultaneously in some embodiments. The self-expansion ofthe foam may drive the polymer into interstitial regions of the bodycavity that otherwise may be difficult to reach. In addition, theself-expanding foam may provide internal compression against the wallsof the body cavity.

In some embodiments, the foaming step is not dependent upon thecross-linking step to form a foaming gas. For example, the foaming stepmay occur due to an introduction of gas separate from the polymermaterial. In some cases, gases comprising air, CO₂, or other materialsmay be introduced into the body cavity via an external source (e.g., asyringe or any other suitable container). This gas may then permeate thepolymer material (or a cross-linked product) to form bubbles within thematerial, which may form the voids in the foam as polymeric materialcross-links around them. In cases where the gas is supplied via anexternal source, the source of the gas may be the same as or differentfrom the source of the polymer material (e.g., 14 in FIG. 1 ).

In some embodiments, the gas may be supplied as a product of a chemicalreaction of part of the polymer or a cross-linked product. For example,in some embodiments, the foaming step comprises reacting one or morependant groups on the polymer or cross-linked product to form a gaseousproduct. The gas-producing pendant groups may react upon contact withanother material in the body cavity. For example, in some cases, the gasproducing groups may react upon contact with moisture in the bodycavity. In some cases, the gas-producing pendant groups may react with achemical supplied to the body cavity separately from the polymermaterial (e.g., via the bloodstream, via an external source separatefrom the polymer material source, etc.). In some embodiments, thegas-producing pendant groups on the polymer chain may react with anothercomponent that is supplied to the body cavity. In some embodiments, thepolymer or cross-linked product may comprise CO₂-producing groups.Examples of CO₂-producing groups include, but are not limited to,isocyanate groups, carbonates, bicarbonates, and carbamates. Such groupsmay produce CO₂ gas when reacted with an acid, for example. In somecases, the CO₂-producing group may include an N-hydroxysuccinimidecarbonate, illustrated below:

CO₂-producing groups may include, in some cases, imidazole carbamates,as illustrated below:

As noted above, in some embodiments, the foaming and cross-linking stepsoccur substantially simultaneously. In some cases, the foaming andcross-linking steps may occur substantially simultaneously, but remainindependent of each other. For example, the polymer material maycross-link by reacting with water in the body cavity, and, atsubstantially the same time, gas may be introduced to the polymermaterial from an external container. In another embodiment, a firstmaterial containing gas generating groups may produce gas by contactwith a second agent (e.g., water in the body, water supplied separately,or chemical additive), while contact or interaction with a thirdmaterial leads to crosslinking. For example, at the time of delivery,polymer A with isocyanate groups can be mixed with water and polymer B,in which the former causes the generation carbon dioxide to foam thematerial and polymer B can contain hydroxyl groups that react withisocyanates on polymer A to form a cross linked network between polymersA and B.

The foaming and cross-linking steps may be, in some cases, part of thesame reaction process. For example, one or more reactions may produce agaseous by-product which serves as the supply of gas to form the polymerfoam, but concurrently leads to the generation of new functional groupsthat enable crosslinking. The gaseous by-product can be trapped withinthe polymer and coalesce to form bubbles. As the reaction progresses,the formation, growth and expansion of the gas bubbles can expand thepolymer volume and force it into interstitial areas of the body cavity.As the polymer cross-links, a three-dimensional foam can be formedwithin the body cavity. The volume expansion and cross-linking can serveto coat and seal surfaces of the body cavity, and optionally provideinternal compression, which may be useful, for example, in stoppingbleeding. In addition, such a reaction scheme can be combined with anexternal supply of gas (e.g., CO₂ in an external container) to increasethe amount of gas contained in the polymer or a cross-linked product ofthe polymer.

FIG. 3 includes an exemplary schematic diagram of a system in whichsimultaneous cross-linking and gas generation occur. Polymers 310 and312 include biodegradable backbones 314. The polymer may also comprise alinker region 316 to attach pendant groups. The polymer may alsocomprise a targeting ligand 318 which can be used to bond the polymer todesired sites (e.g., damaged tissue). In addition, the polymer in FIG. 3includes a cross-linking site 320 that can simultaneously solidify andfoam the material. When the polymer is exposed to a compound 322 (e.g.,water) in the body cavity, gas 324 is released from the cross-linkingsite, which generates a functional group 326 that can react with anotherpolymer to produce a cross-linked structure 328.

All of the foaming mechanisms described herein may occur before anysubstantial cross-linking has occurred or during cross-linking of thepolymer material or a cross-linked product of the polymer material. Forexample, in some cases, an external gas may be introduced into anddispersed within a polymer material that has not substantiallycross-linked. The polymer material may then cross-link around thebubbles to form the foam. In such cases, the viscosity of the polymermaterial can be chosen such that the material is able to retain bubbleswithin the volume without the need for cross-linking. In someembodiments, at least some cross-linking may occur before the gas isintroduced to the polymer material, and the gas is dispersed within apartially cross-linked polymer material that has not completelysolidified to form a foam.

Cross-linking and/or foaming may be achieved, in some instances, usingisocyanate chemistry. Isocyanate groups are relatively unstable whenexposed to water and moisture. Exposure of isocyanate groups to water ormoisture (or other compounds) can lead to the decomposition of thegroups, cross-linking of polymers to which they are attached, andrelease of carbon dioxide, as shown below for a model lysine isocyanate:

In the mechanism above, the isocyanate is partially hydrolyzed toproduce amines, which can react with native, non-hydrolyzed isocyanates,as shown above. Not wishing to be bound by any theory, a cross-linkedstructure can be produced because the rate of the amine-isocyanatereaction may be on the order of or faster than the rate of isocyanatehydrolysis, and inter-chain reactions occur between these functionalgroups to ultimately form a cross-linked structure. The isocyanates onthe polymer can also react with amine groups of the tissue (e.g. lysinesin proteins), which can form a covalent bond with the tissue to furtherstrengthen the seal at sites in which fluid is being lost (e.g., atbleeding sites). In addition, the isocyanate hydrolysis reactionproduces CO₂, enabling simultaneous cross-linking and gas production ina single-reaction scheme.

In certain embodiments, polyurethane foams may be generated bycross-linking polyols with multifunctional isocyanates. Polyols suitablefor use in such embodiments include polyether- and polybutadiene-basedpolyols. Polyols of particular interest include polypropylene glycol(PPG) and polyethylene glycol (PEG), as well as random and blockcopolymers thereof. Also suitable for use are polycarbonates,polybutadienes, and polyesters. Diols, triols, and tetrols are mostpreferred, but multifunctional polyols with any suitable number of armsmay be used. Molecular weights between 100 and 10,000 Da are preferable,with molecular weights up to 6,000 Da being most preferred, and blendsof polymers with different molecular weights, degrees of branching, andcomposition are often used. Commercial polymers of particular interestinclude polypropylene glycols (425, 12001 Da), polyethylene glycols(200, 400, 600, 1000, 2000, 3000 Da), Pluracol products (355, 1135i,726, 816), Arch Poly-G 30-240, Poly-G 76-120, Poly-G 85-29,trimethylolpropane ethoxylate (450, 1014 Da), pentaerythritol ethoxylate(797 Da), UCON 75-H-1400, UCON 75-H-9500, dipropylene glycol, diethyleneglycol, tripropylene glycol, triethylene glycol, tetrapropylene glycol,and tetraethylene glycol. In preferred embodiments, polyols used in thepresent invention have a polyethylene oxide content of 0-50 wt %, morepreferably 0-40 wt %, more preferably 0-30 wt %, more preferably 0-25 wt%, and most preferably 0-16.5 wt %. Also preferred is that polyols usedin the present invention comprise an amine catalyst in an amount up to10 pphp, a water content of up to 20 pphp, a surfactant in an amount upto 10 pphp, and a diluent up to 300 pphp (preferably up to 250 pphp andmost preferably up to 15 pphp). Examples polyurethane foams generated bycross-linking polyols with multifunctional isocyanates, in accordancewith the present invention, are listed in Table 7.

Isocyanates suitable for use in such embodiments include any polymericisocyanate with a degree of functionality greater than 2.0, with themost useful range being 2.0-2.7. Preferred polymeric isocyanates arebased on methylene diphenyl isocuanate (MDI). Isocyanatetrue-prepolymers and quasi-prepolymers may also be used. In this case, a“quasi-” prepolymer, or semi-prepolymer, is a polymer formed by thereaction between a multifunctional isocyanate and polyol, where theisocyanate-to-alcohol ratio is greater than the stoichiometrictwo-to-one ratio. A “true-” prepolymer, or strict-prepolymer, is apolymer formed by the reaction between a multifunctional isocyanate andpolyol, where the isocyanate-to-alcohol ratio is equal to thestoichiometric two-to-one ratio.

In some instances, it may be advantageous to position isocyanate groupsin the polymer so that it is accessible for hydrolysis andcross-linking, without inhibiting binding to the tissue (e.g., damagedblood vessels). In one set of embodiments, a lysine group in thetargeting peptide can be converted to an isocyanate by reaction withdiphosgene. In some instances, the isocyanate and peptide chemistriescan be completely decoupled by modifying a fraction of the side chainswith peptide while the balance are modified with isocyanate.

The polymer that is foamed to form the polymer foams described hereinmay be formed using a variety of chemistries. In some embodiments, thepolymer comprises a synthetic polymer. As used herein, a “syntheticpolymer” refers to a polymer that is a product of a reaction directed byhuman interaction. For example, synthetic polymers can include polymerssynthesized by reactions of natural or synthetic monomers orcombinations thereof that are directed by human interaction. Theformation of synthetic polymers can also include chain elongation ofnatural or synthetic polymers. In some embodiments, the syntheticpolymer is not found in nature. In other cases, the synthetic polymercan be found in nature, but the polymer is synthesized via humaninteraction (e.g., in a laboratory setting). In some embodiments, thepolymer may comprise a poly alpha-hydroxy acid. In some cases, thepolymer may comprise a polyester. In some cases, the polymer maycomprise a polyether-polyester block copolymer. In some cases, thepolymer may comprise a poly (trimethlyene carbonate). In someembodiments, the backbone of the polymer can exclude at least one ofpolynucleotides, proteins, and polysaccharides.

In some embodiments, the polymer foam is formed by cross-linking acondensation polymer of a polyol and a polyacid. The terms “polyol” and“polyacid” are given their standard meanings in the art, and are used torefer to compounds comprising at least two alcohol groups and at leasttwo acidic groups, respectively. Examples of polyols suitable for use informing the condensation polymer used to form the polymer foamsdescribed herein include, but are not limited to, glycerol, polyethyleneglycol, polypropylene glycol, polycaprolactone, vitamin B6, erythritol,threitol, ribitol, arabinitol, xylitol, allitol, altritol, galactritol,sorbitol, mannitol, iditol, lactitol, isomalt, and maltitol, wherein thefunctional groups present on the polyol are optionally substituted.Examples of polyacids suitable for use in forming the condensationpolymer used to form the polymer foams described herein include, but arenot limited to, succinic acid, fumaric acid, a-ketoglutaric acid,oxaloacetic acid, malic acid, oxalosuccinic acid, isocitric acid,cis-aconitic acid, citric acid, 2-hydroxy-malonic acid, tartaric acid,ribaric acid, arabanaric acid, xylaric acid, allaric acid, altraricacid, galacteric acid, glucaric acid, mannaric acid, dimercaptosuccinicacid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipicacid, pimelic acid, suberic acid, azelaic acid, sebacic acid, malicacid, or vitamin BS, wherein the functional groups present on thepolyacid are optionally substituted.

In some embodiments, the condensation polymer may comprise poly(glycerol-sebacate) (PGS). An exemplary synthesis pathway in whichglycerol and sebacic acid are used to form PGS is shown below:

In some embodiments, the polymer foam is formed by cross-linking apolymer comprising the following formula (I):

wherein R₁ and Z can be the same or different and each is an alkyl,heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl,heteroaryl, heterocycle, acyl or carbonyl group, any of which may beoptionally substituted, and wherein n is an integer greater than 1. Insome embodiments, R₁ and/or Z are substituted with a gas producinggroup. For example, R₁ and/or Z may be substituted with a CO₂-producinggroup (e.g., isocyanate).

wherein R₁ and R₂ can be the same or different and each is an alkyl,heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl,heteroaryl, heterocycle, acyl or carbonyl group, any of which may beoptionally substituted; wherein x and y are non-negative integers;wherein R₃ may be a hydrogen, gas generating functional group, or tissuebinding domain.

In some embodiments, the polymer may comprise the poly (lactic acid)(PLA), poly (glycolic acid) (PGA), and polycaprolactone (PCL) class ofpolymers and their copolymers, such as poly (lactate-co-caprolactone) orpoly (glycolate-caprolactone). Copolymerization of the lactide,glycolide and caprolactone monomers in various ratios can yieldmaterials with a wide range of mechanical properties, thermalcharacteristics and degradation times. The structure of the PLA/PGA/PCLcopolymers (and associated properties such as molecular weight, etc.)can be tailored, in some cases, by adjusting the type of initiator usedand its molar ratio with the monomer(s).

In some embodiments, the polymer comprises poly (glycolatecaprolactone). In some cases, the PGCL composition includes a ratio ofglycolide to caprolactone of about 50:50. An exemplary synthesis pathwayfor PGCL is shown below, in which pentaerythritol is used as aninitiator to form 4-armed, branched structures.

The properties of the polymer used to form the polymer foam may betailored to achieve a desired result. For example, in some embodiments,the viscosity of the polymer is tailored such that the polymer is ableto permeate the body cavity and create conformal contact. An overlyviscous polymer may require excessive pressure to deploy within the bodycavity. In addition, an overly viscous polymer may inhibit the polymerfrom accessing interstitial spaces. An overly low-viscosity polymermight be difficult to contain the material to the injured site or may bedisplaced by the flow of a bodily fluid. One of ordinary skill in theart will be able to produce the desired viscosity for a given polymertype by, for example, adjusting the molecular weight of the polymer. Insome embodiments, the viscosity and the molecular weight are relatedthrough a power law. The molecular weight of a polymer may be adjustedby, for example, controlling the time of the polymerization reactionused to generate the polymer. In some embodiments, the molecular weightof the polymer is between about 1000 and about 10,000 g/mol or betweenabout 1200 and 6000 g/mol. The viscosity of a polymer may be adjustedby, for example, adding diluents such as any suitable low molecularweight, low viscosity compound, examples of which include triacetin,propylene carbonate, tetraethylene glycol dimethyl ether, dimethylesters of diacids (e.g., diethyl malonate, dimethyl adipate), dimethylsulfoxide, and oils (vegetable, olive, castor, etc.). In embodimentsthat include polyols, it is preferable to add up to about 300 pphp ofdiluent to control polymer viscosity.

Insome embodiments, the polymer is amorphous or semi-crystalline with aglass transition temperature (T_(g)) below room temperature. Suchproperties yield, in some cases, polymers with sufficiently lowviscosities that they can be dispensed from an external container viapressure-driven flow.

In some embodiments, properties or composition of the polymer may bechosen to achieve a desired hydrophilicity or hydrophobicity. Thehydrophilicity of the polymer may be selected, in some instances, suchthat the surfaces (e.g., tissue surfaces) within a body cavity areappropriately wetted. Generally, a material with increasedhydrophilicity will have a greater tendency to wet soft tissuessurfaces. However, the polymer and resulting polymer foam may be, insome cases, somewhat hydrophobic such that they do not dissolve intobiological fluids. Appropriately hydrophilic polymers are capable ofconformally wetting interior surfaces of a body cavity while remainingcontained within the cavity. In some embodiments, the composition of thepolymer may be selected to achieve a desired hydrophilicity. Forexample, in some embodiments, the chain length of a monomer used tosynthesize the polymer can be varied to change hydrophilicity. As aspecific example, the carbon chain length between carbonyl groups of adiacid monomer can be varied from between two and eight aliphaticcarbons, producing a range of hydrophilicity in the resulting polymer.

In some embodiments, the polymer foams described herein may havefavorable mechanical properties. In some embodiments, the polymer foamsare elastomeric. The term “elastomer” as used herein, refers to apolymer that can return to the approximate shape from which it has beensubstantially distorted by an applied stress. In some cases, theelastomeric polymer foams described herein may comprise a polymer havinga bulk modulus of between about 0.05 MPa and about 10 MPa; 0.05 MPa andabout 100 MPa; and 0.05 MPa and about 500 MPa. Elastomeric polymers maybe particularly suitable for use in making polymer foams because theyare capable sustaining stress without permanently deforming, whileproviding adequate support for body organs and tissues.

The time required to form the polymer foam after exposure to the bodycavity and the final mechanical and physicochemical properties of thepolymer foam can depend on such factors as the composition of thepolymer, the density of pendant groups (e.g., cross-linking groups), andrelative positions of the pendant groups (e.g., cross-linking groups).One of ordinary skill in the art will be capable of adjusting theconcentration and location of pendant groups to produce polymer foamswith desirable physical properties.

In some embodiments, the polymer or polymer foam may be biodegradable.As used herein, “biodegradable” describes materials that are capable ofdegrading down to oligomeric or monomeric species under physiological orendosomal conditions. The phrase “physiological conditions,” as usedherein, relates to the range of chemical (e.g., pH, ionic strength) andbiochemical (e.g., enzyme concentrations) conditions likely to beencountered in the intracellular and extracellular fluids of tissues. Insome embodiments, the physiological pH ranges from about 7.0 to 7.4. Insome embodiments, biodegradable materials are not hydrolyticallydegradable but can be fully degraded via enzymatic action to fullydegrade. In some cases, biodegradable materials are hydrolytically orenzymatically degradable, or combinations thereof. In some embodiments,the polymer or polymer foam is biodegradable, but it does not biodegradeover the time scale in which it is located within a body cavity. In suchcases, the polymer foam can remain structurally stable while beinginserted into the body cavity, while ensuring that any remnants of thepolymer foam that remain within the body cavity after removal can bebiodegraded. For example, in some embodiments, the biodegradable polymerfoam does not significantly biodegrade within the body cavity prior toremoving the foam via surgical intervention.

The polymer or polymer foam may be biocompatible, in some instances. Oneof ordinary skill in the art can determine biocompatibility based uponthe ISO-10993 standard. For example, PGS is known to satisfy theISO-10993 standard for biocompatibility. In some embodiments, chemicalmodifications (e.g., attachment of a pendant group, etc.) to the PGSbackbone do not alter its biocompatibility. In some embodiments, apolymer that produces known, but acceptable levels of inflammation maybe used. Examples of such polymers include poly-alpha-hydroxyacids(e.g., polylactide, polyglycolide, and polycaprolactone) andpoly(trimethylene carbonate).

The polymeric foams described herein may be used, in some embodiments,to prevent or limit the movement of a bodily fluid within the bodycavity, relative to an amount of movement of bodily fluid that wouldoccur under essentially identical conditions in the absence of thepolymer foam. “Essentially identical conditions,” in this context, meansconditions that are similar or identical other than the presence of thepolymer foam. For example, otherwise identical conditions may mean thatthe body cavity is identical, the conditions within the cavity areidentical, but where no polymer foam is located within the body cavity.In some embodiments, the polymer foam may be used to reduce an amount ofbleeding within a body cavity. The polymer foams may also be used toprevent or limit the movement of bile or other digestive fluids,interstitial fluid, or any other suitable fluid. In some embodiments,preventing or limiting the movement of bodily fluid comprisesimmobilizing and/or stabilizing blood clots. Preventing or limiting themovement of a bodily fluid may comprise, in some instances, the movementof bodily fluids into the cells of the polymer foam. Such movement offluid into the cells may aid in the formation of, for example, bloodclots or other stabilizing structures within the foam.

The movement of bodily fluids may be prevented or limited over arelatively long period of time. For example, in some embodiments, thepolymer foam can prevent or limit movement of a bodily fluid within thebody cavity for at least about 3 hours, at least about 6 hours, at leastabout 12 hours, at least about 24 hours, at least about 3 days, or atleast about 1 week.

In some cases, the movement of bodily fluids may be prevented or limitedvia the application of pressure. For example, the formation of thepolymer foam may involve volumetric expansion of the polymer. In someembodiments, the expansion of the polymer may result in the applicationof a pressure to a surface within the body cavity.

In some embodiments, the polymer foam may be used to reduce the amountof bleeding within the wound cavity relatively quickly. This may beimportant, for example, in avoiding hyperfibrinolysis. In some cases,the polymer may be designed to cross-link quickly, for example, bytailoring the polymer to have functional groups that crosslink quickly,by adding catalysts, or by other known means. Suitable catalysts for usein embodiments of the present invention include amine based compounds,preferably tertiary amines, triethylenediamine (TEDA, DABCO, DABCO33-LV), bis(2-dimethylaminoethyl)ether (Niax Al),trimethylaminoethyl-ethanolamine, 1,2-dimethylimidazole. In addition,the pores of the foam can trap blood and allow it to coagulate instagnant areas. In addition, the rate at which the amount of bleeding isreduced can be controlled by adjusting the amount of reactive pendantgroups.

In addition to gas-forming pendant groups, other active agents may alsobe included as pendant groups on the polymer. For example, the polymerfoam can include groups used to stimulate desirable cellular responsessuch as fibroplasia, angiogenesis and epithelialization. In someembodiments, the polymer or polymer foam may be covalently bonded to asurface within the body cavity, for example, through a pendant group.

In some embodiments, the polymer or cross-linked product may comprise atleast one pendant group (e.g., at least one pendant group) that can bindto tissue or injured tissue (e.g., inflamed tissue, bleeding tissue, awound site, etc.) within the body cavity. The binding of the pendantgroups to the tissue or injured tissue can be covalent or non-covalent.The tissue or injured tissue may comprise one or more molecules thatwould not be present in or near uninjured tissue as is the case, forexample, when subendothelial surfaces are exposed. By including suchpendant groups, a polymer or cross-linked product could be made thatselectively binds to tissue or injured tissue, in comparison touninjured tissue. Such binding may limit or prevent the movement ofbodily fluid within the body cavity, in some embodiments. Examples ofchemicals that may be targeted by pendant groups on the polymer orpolymer foam include, for example, von Willebrand Factor, collagen(e.g., collagen I and IV), a fibroblast growth factor, laminin, elastin,localized coagulation factors in their activated form (e.g., fibrin,thrombin, factor Xa, etc.), among others. Example of types of pendantgroups that may be bound to the polymer or polymer foam for such usesinclude, for example, peptides, carbohydrates (e.g., oligosaccharidesequences), aptamers.

One of ordinary skill in the art will be able to identify othercompounds in tissue or injured tissues and perform screening tests todetermine suitable pendant groups that could be used to bind with thosecompounds. For example, in vivo screening, for example by phage displaytechnology, of a large library of possible pendant groups (e.g.,permutations of peptide sequences fused to a phage surface protein, acollection of carbohydrate molecules, etc.) could be performed (e.g., inrodents) to identify pendant groups that bind specifically to woundedorgans. The pendant group could then be identified (e.g., via sequencingfor peptides) from each organ. For example, a sequence that appears inall organs or injured organs could be identified. Subsequent testing(e.g., in vivo testing in uninjured animals) could be performed toverify that the pendant group does not bind to tissue in the absence ofinjury.

In some cases, human protein targets can be used to find pendant groupsthat bind selectively to the injured site. For example, human fibrin,which is generally present where injuries to blood vessels haveoccurred, can be used for screening, potentially mitigating the riskpresent in the in vivo approach where there could be sequence andconformational differences between animal and human targets. Bindinglevels to fibrin can be assessed using, for example, fluorescentlytagged molecules, and compared against, for example, fibrinogen, aprecursor of fibrin that is ubiquitous in blood plasma. The pendantgroups showing highest selectivity to fibrin over fibrinogen could beselected for use in the polymer composition.

In addition to targeting tissues or injured tissues, pendant groups maybe used to stabilize tissue or injured tissue. For example, pendantgroups (e.g., CO₂-forming groups) may covalently bond to tissue, in somecases, which may lead to the sealing of one or more openings within abody cavity. Such binding can aid in limiting or preventing the movementof bodily fluid within the body cavity, in some cases. In someembodiments, the concentration of isocyanate in the polymer or across-linked product can affect the extent to which binding between thepolymer and tissue occurs. Specifically, increasing the isocyanatelevels can serve to increase and reinforce the polymer-tissue contactarea, potentially producing a stronger and longer-lasting seal.Increasing the level of isocyanate in the polymer can also increases thecrosslink density, potentially resulting in a more rigid material thatmay break more easily at the polymer-tissue interface (e.g., when thebody is moved). Therefore, the concentration of isocyanate may beselected, in some cases, to balance between these two effects.

In another embodiment, the polymer properties are selected such thatminimal covalent binding of the foam to tissue is observed. The foam,however, can be bound to tissue by different non-covalent forces, suchas electrostatic, Van der Waals, or capillary. Minimal covalent bindingof foam to tissue can facilitate easy foam removal and preventadhesions, such as abdominal adhesions, during the healing process.

In some cases, non-isocyanate pendant groups may be used to stabilizethe polymer-tissue interface. For example, the polymer may comprisealdehyde reactive groups, which can be used, for example to bind tissueproteins. Aldehyde groups may be attached by, for example, attachingethanolamine to the polymer, followed by oxidizing the pendant hydroxylgroup to form an aldehyde group. In some instances, pendant groups thatselectively bind to fibrin may be used to stabilize the clot-polymerinterface. In addition, pendant groups may be selected that compete withplasminogen and its activators for fibrin binding sites, blocking theactivation of fibrynolytic cascade.

In some embodiments, the polymer (or the compounds used to make thepolymer) are chosen such that they comprise one or more pendant hydroxylgroups. The hydroxyl groups may serve, for example, as sites at whichpendant groups are attached to the polymer. For example, glycerol andsebacic acid both contain hydroxyl groups that may be used to impartfunctionality to PGS. As a specific example, pendant peptides can beintroduced onto polymers using a two-step reaction scheme in which thepolymer hydroxyl groups are first activated with carbonyldiimidazole(CDI) and then coupled to the amine-terminus of the peptide, as shownbelow. This chemistry can result in high coupling efficiencies.

In some instances, a drug may be delivered to the body cavity with thepolymer. In some embodiments, the polymer may comprise a drug. Forexample, a drug (or a plurality of particles containing one or moredrugs) may be dispersed within the polymer. Example of such drugsinclude, but are not limited to, antifibrinolytic compounds (e.g.,aminocaproic acid, tranexamic acid, etc.), anti-fibrotic compounds,antimicrobial compounds (e.g., antibiotics), anti-inflammatorycompounds, analgesics, pro-coagulant compounds, growth factors, andvasoconstrictors. Drugs that comprise amine groups may, in some cases,be isolated from isocyanates within the polymer, for example, to preventunwanted reaction during the cross-linking step. Isolation can beachieved by encapsulating drugs into secondary particles and loadingthem into the polymer at the time of delivery to the body cavity. Inaddition, encapsulation may be used to release the drugs at a controlledrate. In some embodiments, a drug may be incorporated into a fiber,which may be included in the polymer. The drug release rate from thefiber can be controlled by varying composition and structure (e.g.,thickness or other dimension, presence of sheath) of fiber. For example,the fiber can be designed to deliver an initial burst release shortlyafter the deployment of the polymer, followed by sustained delivery(e.g., over the time period in which the polymer foam will be left inthe body cavity).

The polymer may be combined with a second agent (and, optionally, athird agent, fourth agent, etc.), in some cases, before or after thepolymer is transported to the body cavity. The second agent maycomprise, for example, a compound that accelerates at least one ofcross-linking and foaming, relative to a rate of at least one ofcross-linking and foaming that would have occurred in the absence of thesecond agent. For example, in some embodiments, the second agent maycomprise an amine (e.g., a polyamine). The amine compound may serve toincrease the rate at which the polymer cross-links, which may alsoreduce the amount of time required to reduce or eliminate the movementof a fluid (e.g., blood) within the body cavity. The second agent maycomprise, in some cases, at least one of lysine, spermine, spermidine,hexamethylenediamine, polylysine, polyallylamine, polyethylenimine, andchitosan. In some cases, the second reagent may comprise a carbonate ora bicarbonate which may be used, for example, to produce CO₂ gas insitu, as described above. In some embodiments, the second reagent cancomprise an acid which may be used, for example, as a reactant in theCO₂-producing reaction. The acid functionality may comprise, forexample, a carboxylic acid pendant group attached to a polymer chain orblended with a polymer to form a mixture. In some cases, the secondreagent can be native in the body (e.g., bicarbonate in the blood). Inother cases, the second agent may originate from outside the bodycavity. For example, the second agent may be, for example, supplied tothe body cavity along with the polymer.

In some embodiments, the combination of the second agent with thepolymer produces a polymer foam with significantly different mechanicalproperties (e.g., elastic modulus, yield strength, breaking strength,etc.) than would have been produced in the absence of the second agent.For example, addition of the second agent may lead to increasedcross-linking among polymer molecules, potentially producing a stifferfoam.

The combination of the second agent with the polymer may, in someembodiments, prevent or limit bleeding within the body cavity, relativeto an amount of bleeding that would occur under essentially identicalconditions in the absence of the second agent. In some embodiments,bleeding may be reduced due to the increased rate of cross-linking orfoaming mentioned above. In some cases, the second agent may comprise apro-coagulant compound (e.g., thrombin, fibrinogen, factor X, factorVII).

The second agent may be stored in a container separate from the polymer,for example, to prevent unwanted reaction between the polymer and thesecond agent outside the body cavity. In some embodiments, a containercan be used that keeps the polymer and the second agent separated whilestored or transported, but allow for mixing at the outlet nozzle orwithin the body cavity when the contents are expelled. The outlet nozzlecan mix multiple components (>2) including gases in a static or dynamicmanner. Examples of static mixers are Low Pressure Drop (LPD) mixers,Bayonet mixers and Interfacial Surface Generator (ISG) mixers. Examplesof dynamic mixers are impellers, and rotary static mixers. Nozzles willhandle low and high pressure differentials during dispensing. Thecontainer may also be designed to mix the components immediately priorto dispensing by breaking the barrier between each of the components andallowing them to mix. Mixing can occur manually such as shaking thecanister or chambers can be under vacuum and when the barrier is brokena vortex will be created to mix the components.

In another embodiment, additives can be added to the polymer that absorbthe heat generated during the cross-linking reaction. For example,materials in the form of micro or nano-particles, spheres or fibers canabsorb the heat by undergoing a phase change (e.g. melting) or glasstransition and thereby reduce the heat absorbed by biological tissues.For example, biodegradable fibers made of polycaprolactone can melt at−60° C., absorbing the generated heat and reducing tissue damage.

In some embodiments, the body cavity can be imaged. The ability to imagethe body cavity can allow for efficient localization and repair of aninjury, stabilization of a wound, etc. In some embodiments, pendantgroups on the polymer or polymer foam can be utilized to aid in imagingthe body cavity. For example, a contrast agent can be introduced intothe blood stream of a subject in which the body cavity is located, andthe contrast agent may be capable of selectively binding to pendantgroups of the polymer. Examples of contrast agents include, for example,colored, fluorescent, or radio-opaque imaging entities. In someembodiments, the contrast agents emit electromagnetic radiation in thenear-infrared range (e.g., about 700 to about 1000 nm) upon interactingwith the polymer foam. As a specific example, quantum dots (QD) may beused as contrast agents. In some cases, fluorescent organic tags (e.g.fluoroscein isocyanate) or radio-opaque chelating groups (e.g., Gd3+)can be used with appropriate imaging equipment. In another example, thecontrast agents listed above may be attached as pendant groups to thepolymer or dispersed in the polymer to aid in visualization.

A variety of mechanisms can be employed to remove polymer or polymerfoam from the body cavity or from placement on tissue. In someembodiments, at least part of the polymer foam is removed via surgicalintervention. For example, the polymer foam may be cut out of the bodycavity, in some instances. In some cases, surgical intervention may besufficient to remove the bulk of the polymer foam material (e.g., atleast about 80%, at least about 90%, etc.) from the body cavity. Thepolymer or the pendant groups bonded to the polymer may be selected, insome cases, such that the resulting polymer foam can be removed from abody cavity. In some embodiments that employ a biodegradable polymer orpolymer foam, the foam or the remainder of the foam after surgicalremoval may biodegrade over time.

In some embodiments, the foam may be degraded by applying an externalstimulus to the foam. Such methods may be useful, for example, when somepolymer or polymer foam material remains physically inaccessible aftersurgical removal due to, for example, deep tissue penetration. Examplesof external stimuli that may be applied to degrade the polymer foaminclude, but are not limited to, UV radiation, heat, or a chemical(e.g., a chemical introduced into the blood stream of a subject in whichthe body cavity is formed).

Degradation of the polymer foam may be achieved, in some cases, viareversible crosslinks in the polymer or polymer foam. In some cases, thetype of cross-link or external stimulus type can be selected such thatthe polymer foam is selectively and controllably depolymerized. Uponreversion to the uncrosslinked state, the polymer or polymer foam can,in some cases, be removed from the cavity using, for example, saline.

Reversible cross-linking can be accomplished by, for example, modifyinga pendant group of the polymer to include bis(2-isocyanatoethyl)disulfide. Such chemistry may be particularly useful, for example, whenisocyanate chemistry, which may not be reversible using the externalstimulus of choice, is used to foam the polymer. The disulfide group canbe readily cleaved with, for example, glutathione. In this example, thesulfur-sulfur bond can be broken through a disulfide exchange reaction,enabling selective cleaving at the disulfide bonds by application of,for example, a glutathione solution. As another example, cinnamic acidgroups can be attached to the polymer such that reversing thecross-links can be accomplished by application of UV light.

In some embodiments, the polymer foam is not formed within the bodycavity, but rather, the foam is formed outside of a body cavity, and islater inserted into the body cavity. For example, FIGS. 4A-4C includeschematic illustrations of the formation of a polymer foam within amold. In FIG. 4A, mold 400 is illustrated. FIG. 4B illustrates the stepof supplying polymer 412 to the mold via source 414. FIG. 4C illustratesthe expansion of the polymer to form a polymer foam upon supplying a gasto the polymer. The polymer may, in some case, expand to conform to theshape of the mold. The molded polymer then may be inserted into a bodycavity. In still further embodiments, the polymer may be formed into apolymer foam outside of a body cavity and without the use of a mold. Thepolymer foam may then be formed into an appropriate shape by using anappropriate method such as, for example, cutting, grinding, or any othersuitable method.

In another aspect of the present invention, polymer foams are used toprevent tissue adhesions. These include, but are not limited to fibroticscars that form between tissues following an injury or surgicalintervention as well as other tissue adhesions known to those ofordinary skill in the medical arts. Examples of regions of the bodywhere adhesions have been described include: the abdomen, pelvis, spine,cardiothoracic space and joints as well as at other locations within thebody. These tissue adhesions cause serious clinical consequences. Forexample, irreversible bowel obstruction in the abdominal cavity,infertility in the pelvic region, chronic pain following back surgeryand pain and limited mobility following joint surgery as well as otherdebilitating disorders known to those skilled in the medical arts.

To prevent tissue adhesions, embodiments of the polymer foam areadministered at or near tissue following damage or surgery. Bycontacting the tissue surfaces with the foam and allowing its expansion,folds and inaccessible surfaces are also covered when direct applicationis not possible. The polymer's expansion ratio, compliance,hydrophobicity, viscosity and curing time may be optimized for each bodyregion in order to facilitate complete coverage. The volume of polymerfoam required may also be varied depending on anatomical location andthe area of tissue damage. In some embodiments, the amount of foamadministered may be at least 1 ml, at least 10 ml, at least 100 ml, ormore. In another embodiment, foam expansion is minimal permitting thevolume administered and other delivery factors lead to completecoverage.

All polymer formulations described are contemplated for use inpreventing tissue adhesions. A preferred embodiment utilizes PGS as acomponent of the foam. A more preferred embodiment includesisocyanate-functionalized PGS that cures in the presence of body water.In this embodiment, interchain hydrogen bonding results in an increasein modulus. In another embodiment water may be mixed with theisocyanate-functionalized PGS during administration to facilitatecuring. In another embodiment, the isocyanate-functionalized PGS ismixed at the time of administration with a polyamine (e.g. lysine,PEG-amine). This polyamine acts as a curing or crosslinking agent.Variation in the amount of polyamine and/or type of polyamine usedenables control of mechanical properties of the cured polymer.

In another embodiment, PGS acts as a polyol and can be mixed with anisocyanate containing compound to form a cross linked foam. In thesecases, foam formation is obtained and enhanced by mixing gas into theformulation to create pore nucleation sites, or by adjusting the levelsof surfactants that stabilize the foam pores during their formation andexpansion. In other embodiments, the polymer does not foam or foamsminimally allowing for flow over the tissue surfaces. This allows forcuring into a gel coating. In these cases, PGS is cross linked underconditions that minimize foam formation by limiting or preventing gasinto the formulation and/or reducing the levels of surfactants resultingpore stabilization. In addition, PGS can be gelled or cross linked bymixing with a component that does not generate a gaseous by-productsupon reaction with PGS.

In yet other embodiments two or more different PGS polymers can becombined during administration. These polymers then react and crosslinkinto a gel or foam. The type and ratio of PGS polymers used impact thefoaming, gelling, curing and mechanical properties.

In another embodiment drug-loaded objects are incorporated in the foamor gel at or before administration. Incorporation of drug-loaded objectsinto a polymer during administration is accomplished by those methodsknown to those skilled in the medical and pharmaceutical formulationarts. Examples of drug-loaded objects include: microspheres,microfibers, core-sheath microfibers, core-sheath nanofibers,nanoparticles, nanospheres, nanofibers or pure particles of drug.Preferably drug is released from these objects over a period of 7 days.More preferably the drug is released up to 14 days. Drug may be releasedfor up to 30 days or longer. Preferably the kinetic release profile forthe drug provides approximately the same dose of drug throughout a givenperiod of time.

In certain embodiments, the invention relates to liquid formulationsthat are delivered to a body cavity and form foam implants in situ. Theliquid formulation or formulations optionally include an entrained gasor a dissolved gas. In preferred embodiments, the resulting foam implantprovides hemostasis when applied near one or more sites of hemorrhage.Foam implants of the invention are preferably biocompatible,bioabsorbable, can be removed from the body with standard surgicalprocedures, and do not induce adhesions.

In certain embodiments, the invention is a polyurethane foam that isformed in situ from a two-part formulation as previously described. Thefirst part of the formulation includes an isocyanate compound such ashexamethylene diisocyanate (HDI), toluene diisocyanate (TDI), methylenediphenyl diisocyanate (MDI) or a mixture of MDI isomers, polymeric MDL,isocyanate-functionalized prepolymer, or a polymeric isocyanate having afunctionality of preferably between 2.0 and 3.0. The second part of theformulation includes a hydroxyl-functionalized polymer (polyol). Thepreferred viscosity of the first and second parts of the formulation is1 to 3,000 cP, and preferably about 2,400 to about 2,600 cP. The polyolphase optionally has multiple polyol species, catalysts, surfactants,chain extenders, cross linkers, pore openers, fillers, plasticizers andwater. Air, carbon dioxide or other auxiliary blowing agents areoptionally entrained into either the isocyanate or polyol phases priorto delivery to the patient or, alternatively, are introduced duringdelivery as a component of the formulation.

The invention will be better understood in the context of certainadvantageous characteristics exhibited by foams and formulations of theinvention: (i) transport to sites of injury; (ii) lack of interferencewith bodily functions; (iii) facilitation of hemostasis; and (iv)creation of seals at sites of injury.

Transport to Sites of Injury:

In certain embodiments, foams of the invention reach sites of injurylocated within tortuous body cavities, around or across anatomicalfeatures, through pooled blood, and/or against the flow of blood. Inthese embodiments, the formulation can be deposited at a site within abody cavity, which site is optionally either proximal to or remote froma site of injury that will be treated; the foam will then travel beyondthe site of deposition as foaming and expansion is initiated, forexample by moving and expanding along a path of least resistance. Theformulation and the foam can be miscible with water, and/or hygroscopic.In certain embodiments, miscibility and hygroscopy are improved bytailoring the pore architecture of the foam to induce capillary action,for example by creating an open-pore architecture within the foam, as isdiscussed more fully below. In certain preferred embodiments, themobility of the formulation is facilitated by at least one of thefollowing characteristics: high expansion (10-40× (more preferably25-35×), or foam density between 1.5-6.3 pounds per cubic foot (pcf));low viscosity (less than 3,000 cP); foam pore sizes between 10 μm and 10mm, and hydrophobicity.

With respect to density and expansion, foams have been developed havingdensities between 10 and 1,000 kg/m³, or having expansions of between 1and 95 fold, as shown in FIG. 5 . In general, increasing the waterand/or isocyanate content of the formulation tends to increase thevolume expansion. Without wishing to be bound to theory, it is believedthat this is due to increased blowing and CO₂ evolution. For example,the relatively low 3× expansion of formulation AM203 is increased to 26×in formulation AM201 by increasing the water level of the formulationfrom 0.45 to 7.2 parts per hundred polyol (pphp). Alternatively,increased expansion can be obtained through the use of blowing catalystsincluding bis(2-dimethylaminoethyl)ether (DMAEE) andpentamethyldiethylenetriamine (PMDET), or through the use of catalyststhat increase both blowing and gelling including triethylenediamine(TEDA), typically up to 10 pphp. For example, the relatively low 12.5×expansion of formulation AM237 is increased to 57.5× in formulationAM244 by increasing the level of TEDA from 0.4 to 3.2 pphp. It may bepreferable to increase stabilization of the polymer when the use ofcatalysts results in increased expansion. Such increased stabilizationcan be achieved, for example, by adding surfactants such as Tegostabproducts (B8629, B9736 LF, 4690, 8871, 8523) and Pluronic products(F-68, F-127); adding more gelling catalysts such as heavy metalcatalysts such as stannous octoate and zinc octoate; or with otheradditives such as solid ammonium bicarbonate. For example, formulationAM251 exhibits 95× expansion and is formulated with high water andcatalyst levels and a high isocyanate index.

With respect to hygroscopy and miscibility with water, the waterabsorption characteristics of foams can be tailored as well. Foams havebeen developed having both high and low water absorption, as tested by a4-minute water immersion test. Results of this test for certainformulations of the invention are depicted in FIG. 6 . Water absorptionof foams of the invention range between 0 and 22 grams of water absorbedper gram of foam. In certain embodiments, high water uptake is achievedby creating a highly open cell or reticulated foam structure. Thisarchitecture is formed by balancing the viscosity of the formulation,the rates of blowing and gelling, the catalyst and surfactant types andlevels. Additionally, in certain formulations of the invention, thewater content is preferably high (5-10 pphp), the isocyanate index ispreferably low (10-50 pphp), and a high-functionality isocyanate ispreferably used to provide sufficient crosslinking and rigidity at lowconcentrations to stabilize the foam and prevent collapse. For example,formulation AM373 has a water uptake of 19.8 grams per gram of foam(g/g). The formulation includes a pore opening ingredient (Ortegol 501),a mixture of three polyols for optimal viscosity (Plurcol,trimethylolpropane ethoxylate, and Poly-G) and crosslinking density, anda high-functionality isocyanate (Lupranate M20). Small changes to thelevel of Ortegol 501, the amount of water (<0.8 pphp), or the isocyanateindex (25-35) in the formulation can dramatically decrease the wateruptake characteristics of the foam, even though a reticulated foamarchitecture may still be formed. Compare, for example, formulationAM368, which has water uptake of 6.4 g/g but which retains thereticulated architecture. Thus, it is believed that foam compositionaffects water uptake apart from its effects on pore morphology or foamarchitecture. As another example, formulation AM376 exhibits high wateruptake and has a reticulated architecture. The formulation includes ahydrophilic polyol, trimethylolpropane ethoxylate 1014 Da (46 pphp) andhas high water uptake (19.7 g/g).

In general, the hydrophilicity of the foam may be improved by increasingthe amount of polyethylene glycol (PEG)-based polyols used in theformulation relative to hydrophobic polyols such as those based onpolypropylene glycol. Water uptake of foams may also be increased as thePEG-based polyol content is increased, though some rebalancing ofcatalyst, surfactant, isocyanate and other components may be necessary.Small changes to minor ingredients can significantly improve wateruptake. For example, by increasing the surfactant level of formulation122-009-7 by 2.5-fold, water uptake is increased from 6.7 g/g to 21.7g/g (compare foam 122-009-10).

Transport to sites of injury may also be improved by providingformulations that can disperse within a body cavity before foamingand/or cross-linking. Delayed foaming and/or cross-linking permitslow-viscosity formulations of the invention to penetrate more deeplyinto tortuous spaces within body cavities. Once the formulation isdispersed, foaming may occur at a moderate rate (on the order of lessthan 4 minutes) to fully distribute the foam to reach a site or sites ofinjury. Formulations have been generated that have a variety of reactionkinetics, as measured by cream time, gel time, and rise time and asshown in FIG. 7 . Cream time is defined as the time between the start ofmaterial mixing and the point at which fine bubbles begin to appear andthe foam begins to rise. Gel time is defined as the time at which long“strings” of tacky material can be pulled away from the surface of thefoam when the surface is contacted with the edge of a tongue depressoror similar instrument. Rise time is the time at which the foam stopsexpanding as observed visually.

Foaming kinetics can be altered by adjusting the types and levels ofcatalysts and inhibitors used in the formulation. In general, theaddition of weak acids such as acetic acid or citric acid delays thestart of foaming, but has a limited effect on the rate of foaming onceit begins. The rate of foaming can be controlled by adjusting therelative levels of blowing and gelling catalysts. For example, the startof foaming is significantly delayed in formulation AM096 (cream time of25 seconds, rise time of 105 seconds), but the rate of foaming remainssimilar relative to formulation AM099 (cream time of 9 seconds, risetime of 95 seconds), yet the two differ only in that the level of aceticacid is 0.5 pphp higher in AM096 than in AM099. Generally, preferredembodiments of the invention maximize cream time and minimize rise timeto yield cream times of 15 seconds and higher, and rise times of up to150 seconds.

The viscosity of formulations of the invention can also be controlledand, without wishing to be bound to any theory, it is believed thatlower viscosity of the isocyanate and polyol phases improves dispersionwithin the abdominal cavity. Conventionally, polyols used inpolyurethane foam formation are multi-functional, OH-terminated polymerswith viscosities of between 250 and 5,000 cP. Because high weightpercentages are typically used in the art, polyol phases used in foamformulations tend to have similar viscosities. Formulations of theinvention, however, may achieve substantially lower phase viscosities byseveral means, including (i) using higher quantities of water to dilutehigh-viscosity polyol components; (ii) using low molecular weight (andhence lower viscosity) polyols; and (iii) using non-reactive diluents tothe polyol phase. With respect to diluting high-viscosity polyolcomponents with water, a range of water concentrations of 10-20 pphp maybe useful for two-part foaming formulations, while in systems usingisocyanate prepolymers water levels of 50-100 pphp are preferred. Withrespect to using low molecular weight polyols, preferred compoundsinclude propylene glycol, di- tri- and tetra-propylene glycols, ethyleneglycol, di- tri- and tetra-ethylene glycols, and low molecular weight,linear or multi-armed, hydroxyl-terminated polymers preferablycontaining 1-10 repeat units such as polypropylene glycols, polyethyleneglycols, polytetrahydrofurans, polytetramethylene glycols, andpolydimethylsiloxanes. As for non-reactive diluents, between 10-200 pphpof diluent may be added to the polyol phase, and it has been found thata level as high as 300 pphp can be added to some formulations to yieldstable foams (e.g. formulation AM1042; 5.6× expansion). Preferredproperties for diluents include low viscosity (<50 cP; more preferably0.5-10 cP), lack of reactivity towards hydroxyls, isocyanates, and othercomponents in the formulation, and biocompatibility. Preferred diluentsinclude propylene carbonate (PC), diethyl malonate, tetraethylene glycoldimethyl ether (TEGDME), and triacetin.

Using low molecular weight polyols and/or diluents, polyol phases havebeen engineered with viscosities ranging from 17 cP (AM1045) to 2635 cP(AM735). For example, the hydrophobic polyol phase of formulation AM880(53 cP) combines a low viscosity polypropylene glycol (1200 Da) and thediluents diethyl malonate (15 pphp) with other ingredients. The morehydrophilic polyol phase of formulation AM759 (50 cP) combinestrimethylolpropane ethoxylate (1014 Da) with 70 pphp TEGDME and otheringredients. Even with high levels of diluents, foams with highexpansion can still be produced (AM1209; 41 cP; 60 pphp TEGDME; 38×expansion) by increasing the catalyst, water, and isocyanate levels.

Using even higher diluent levels (100-300 pphp) enables furtherreduction of viscosity (e.g. formulation AM1045; 17 cP; 150 pphp PC;12.1× expansion). In formulations with high levels of diluents, it isnoticed that a heterogenous cell structure with large, irregular cellstypically forms at the foam base. The addition of ammonium bicarbonate(0.5-20 pphp) can eliminate this heterogeneity. Using ammoniumbicarbonate together with high levels of diluents, foams can begenerated with >20× expansion (AM1055; 150 pphp PC; 21.8× expansion).Additionally, added diluents may advantageously act as plasticizers andlead to foams with low compression-force at 50% deflection values (CFD),as discussed below (e.g., AM761; 70 pphp TEGDME; 25.8× expansion, 0.3kPa CFD).

An in vitro test to evaluate dispersion and movement of formulations ofthe invention has been developed, and is shown schematically in FIG. 8 .In the test, a tube is placed within a closed container, a plastic bag.A pump is connected to the tube, and a small hole placed in the tube tocreate a fluid flow orifice. The tube is submerged within a pool ofwater of known volume. A formulation is tested by delivering it to theplastic bag using a delivery system and, after a selected periodelapses, examining the behavior of the formulation by evaluating, amongother things, the apposition to the small hole in the tube, the volumeof expansion, and the amount of water absorbed during the blowing,gelling, and curing process. A range of formulations have been examinedin this in vitro transport test, and a range of outcomes have beenobserved. Some formulations have advanced and made conformal contactwith the flow orifice (e.g. AM096, AM593). In these formulations, thematerial around the fluid flow did not contain any gaps, tunnels, orflow pathways that indicated poor transport. For example, formulationAM005 was successful in the transport test; the material contacted theflow orifice and was well apposed. The apposition was close enough tocreate a dimple in the material from the flow orifice, as shown in FIG.9 . Other formulations have not advanced to the flow tube, or have notmade conformal contact with the flow orifice (e.g. AM289, AM374, AM244,AM735). Finally, certain formulations displayed an intermediate result,where the flow orifice is partially covered or has a tunnel path offluid escape through the material (e.g. AMI 13, AM315, AM746).

A range of formulations have been successful or partially successful inthis transport test. Low viscosity, delayed reaction kinetics, and highexpansion are all correlated with success in the test. The majority offormulations that have been successful in the test (conformal ornear-conformal contact with the flow orifice) have had a viscosity ofless than 1200 cP, cream time of more than 10 seconds, and expansiongreater than 12×. Finally, hydrophobic formulations have generallyperformed better in the test than hydrophilic formulations.

An in vivo test of formulations of the invention has also beendeveloped, utilizing a porcine model of grade V splenic hemorrhage inwhich formulations are deployed in a closed abdominal cavity. FIG. 10shows foams of the invention deployed in vivo. A semi-quantitativescoring system has been developed for the assay to evaluate transport ofthe formulations and is outlined in Table 1. Table 2 summarizes theperformance of certain formulations in the in vivo transport assay andincludes a “Net apposition score” for each. Based on their performancein the assay, formulations were clustered into two groups of high andlow scores. Foams with net apposition scores greater than 10 were allhydrophobic (less than 30 pphp PEG), had medium-to-high expansion ratios(13-33×), low-to-medium water uptake levels (12-46%), and with theexception of one formulation, had slow cream times (10-57 seconds).Characteristics of high-scoring formulations are presented in Table 3.By contrast, low-scoring formulations—those with net apposition scoresless than 6—were hydrophilic (more than 70 pphp PEG), had low expansion(8-16×), and high water uptake levels (80-95%), as shown in Table 4.

Lack of Interference with Bodily Functions:

Foams of the invention are preferably soft and easily compressed so thatthey do not interfere with physiological functions such as respirationor cardiac output. For example, in preferred embodiments the foams aresufficiently soft so that, when deployed abdominally to form an implant,they do not interfere with venous blood return through the inferior venacava. In preferred embodiments, the foams are characterized by CFDvalues less than 25 kPa and require less than 60 mJ to be compressed65%. Foams having CFD values greater than 25 kPA but less than 60 kPAmay be useful in the invention as well.

The foams preferably apply less than 20 mmHg of pressure duringlong-term use, though the foams may transiently apply pressures inexcess of 20 mmHg during the generation and subsequent dissolution ofC02 gas from the isocyanate-water reaction without negative long-termconsequences on bodily functions.

Foams have been developed having CFD values between 0.3 and 100 kPa, asshown in FIF. 11. Soft foams, having low CFD, can be produced usingseveral strategies: (i) using low functionality isocyanates (close to2.0) so that the crosslink density is minimized, (ii) under-indexing theisocyanate (10-80) so that there is a large excess of polyol and minimalcrosslinking, (iii) increasing the polyol molecular weight so that themolecular weight between crosslinks is maximized, (iv) using severalpolyols to break symmetry and molecular stacking, (v) changing thepolyol type to mimimize hydrogen bonding and other intramolecularinteractions, (vi) increase expansion as outlined above, and (vii)adding plasticizers. An example of a low CFD foam that has beendeveloped is AM376, which takes advantage of drastic isocyanateunder-indexing (25) to achieve 0.8 kPa. AM474 is another low CFD foam ofinterest (2.3 kPa), which is made by moderate under-indexing (70) of alow functionality isocyanate (Mondur MRS-2), in combination with fourpolyols to break symmetry. In addition, AM761 is an example of a low CFDfoam (0.3 kPa) made by under-indexing the isocyanate (31) and addingdiluent to plasticize the matrix (70 pphp TEGDME). Without wishing to bebound to any theory, it is believed that modification of the catalyst,surfactant, water, and additive levels can also lead to significantreductions in the CFD. For example, the CFD of 122-001-10 (4.7 kPa) canbe reduced over three-fold by changing the surfactant type and levels toproduce AM479 (1.3 kPa).

Foams having a range of CFD values, as set forth in FIG. 12A, have beentested in vivo and intra-abdominal pressure and peak ventilation airwaypressure have been measured to assess interference with bodilyfunctions, as shown in FIGS. 12B-C. Three foams tested transientlyexceeded an intra-abdominal pressure of 20 mm Hg and two foams exceededa peak airway pressure of more than 10 cm H20 from baseline. Those foamshad intermediate CFD (5-7.5 kPa), but higher expansion ratios (24-33×).Lower CFD materials, such as AM374, AM094, and AMI 13, did not result ina significant increase in pressure.

During the in vivo testing, no effects on cardiac function were observedto be caused or exacerbated by the experimental injury alone.

Facilitation of Hemostasis:

Foams of the invention promote hemostasis when brought into contact withsites of bleeding. In preferred embodiments, foams of the invention havecell and pore structures with characteristics (including size,morphology, and tortuosity) that permit blood to enter the foam butwhich provide resistance to blood flow. In general, small wounds tend toclot and achieve homeostasis quickly and reliably, while larger woundsdo not. High flows from larger wounds are thought to inhibit clotting bydisrupting nascent clots and diluting activated clotting factors beloweffective concentrations and, in larger wounds, clots must reach largersizes. Without wishing to be bound to theory, foams of the invention mayinduce hemostasis by changing the “large wound dynamic” to one of manysmaller wounds which can clot normally, thus inducing hemostasis.Without wishing to be bound to theory, hemostasis is thought to beinduced by foams of the invention through several mechanisms. First, byreducing blood flow, the foams may assist coagulation and allow stableclots to form. In addition to flow resistance, the foams may providehigh polymeric surface area for surface fouling, platelet and cellattachment and activation, and initiation of the coagulation cascade.The preferred properties of the foam to facilitate hemostasis include anopen cell structure with pore sizes of 0.01-1 mm, high expansion(greater than IO×, or foam density less than 6.2 pct), and a highsurface-to-volume ratio. Finally, an additional benefit of providing afoam which allows some blood flow into the structure is a reduction ofpressure and the exertion of less force on any seal which may be createdbetween the foam and the site of injury as compared to a foam which doesnot allow some flow.

Foams have been developed with high flow resistance, as determined bymeasuring the pressure drop needed across a length of foam (P/L) tomaintain a certain volumetric flow rate, as shown in FIG. 13 . Whilemany foam properties can contribute to hydraulic resistance, thecombination of pore size and pore density in particular have been shownto affect resistance. For example, formulations AM219 (tlP/L=8.0mmHg/cm) and AM289 (ilP/L=13.6 Hg/cm) exhibit high flow resistance buthave low pore density (11-13 pores/mm²) and small pore size (avg<130μm). In contrast, formulations AM374 (tlP/L=1.0 mmHg/cm) and AM376(tlP/L=1.1 mmHg/cm) have low flow resistance but have high poredensities (>20 pores/mm²) and large pore sizes (avg>240 μm). However,small pore size and low pore density, alone or in combination, are notnecessarily sufficient to achieve high flow resistance. For example, theformulation AM474 has low pore density (8 pores/mm2) but a large poresize (avg 225 μm) and has low flow resistance (t1P/L=1.5 mmHg/cm).Similarly, formulation AM368 has a small pore size (avg 130 μm) but arelatively high pore density (19 pores/mm2) and low flow resistance(tlP/L=1.7 mmHg/cm).

Pore density (defined as the number of open pores per unit area) can becontrolled by adjusting the types and levels of ingredients in theformulation. In general, pore density can be altered by balancing theisocyanate index, surfactant levels, catalyst levels controlling bothblowing and gelling rates, and the polyol viscosity. In many cases,subtle changes to a single ingredient level can drastically change thepore density. For example, it has been found that decreasing theisocyanate index from 45 (in formulation 126-52-4, which has 7pores/mm2) to 35 (in formulation AM368 which has 19 pores/mm2) whileleaving other component concentrations essentially unchanged results ina significantly higher pore density and openness to the structure. In asimilar fashion, the pore density of formulation 126-52-2 (12 pores/mm2)can be increased to 19 pores/mm2 (AM368) by only adding 0.37 pphp of thepore opening agent Ortegol 501 to formulation.

Similar to pore density, pore size is affected by a number of ingredienttypes and levels. For example, the pore size of formulation AM375(average pore size of approximately 120 μm) can be increased almostthree-fold (in AM376; average pore size of approximately 350 μm) byadjusting the relative ratio of Pluracol 816 to TMPEO (17.5:1 to 1:1)while leaving other concentrations essentially unchanged.

The effect of the hydrophilicity or hydrophobicity of foams on thefacilitation of hemostasis has also been examined, and is discussedbelow. The hydrophilicity or hydrophobicity of foams is controlled asdiscussed above.

Hemostasis has been evaluated in as presented in FIG. 15 . Values inFIG. 15 are presented in grams of blood lost per kilogram body weight.Of nine foams tested, seven had blood loss values lower than the averageof the controls (17.9±5.3 g/kg). Based on the distribution blood lossvalues, the foams were grouped into those with low normalized blood loss(less than the mean blood loss of the controls) and those with highnormalized blood loss (greater than the mean blood loss of thecontrols). Characteristics of materials in the “low” and “high” bloodloss categories are presented in Tables 5-6. Without wishing to be boundto theory, it was noted that there is some overlap in the compositionsof foams exhibiting high “net apposition” in the in vivo assay as shownin Table 2, and foams exhibiting low blood loss as shown on Table 5 [andFIG. 13 ], and there is also some overlap in the composition of foamsexhibiting low “net apposition” and high blood loss, as shown in Table6. For example, formulations AM654 and AM095 both fall in the “highblood loss” and “low net apposition” categories, and both arehydrophilic with low to medium expansion in vivo and high water uptakelevels. By contrast, formulations having “low blood loss” and “high netapposition” scores tended to be hydrophobic, have high expansion, slowcream times and low water uptake. No correlations were observed betweenthe degree of blood loss and pore morphology.

Creation of Seals at Sites of Injury:

Foams of the invention may also create a seal when they reach a site ofinjury, as discussed above. In certain embodiments, sealing isaccomplished by non-specific and non-selective binding of isocyanates inthe formulation with exposed tissue surfaces. In other embodiments,sealing can be targeted to certain sites of interest such as exposedbasement membranes through targeting means.

In some embodiments, a kit including one or more of the compositionspreviously discussed (e.g., a kit including a polymer that can be foamedin situ, a kit including a polymer foam, a device comprising a polymeror polymer foam and any other additive (e.g., external gas, secondagent, etc.), a kit comprising a polymer or polymer foam and a deliverysystem) that can be used to create and/or deploy a polymer foam, or thelike, is described. A “kit,” as used herein, typically defines a packageor an assembly including one or more of the compositions of theinvention, and/or other compositions associated with the invention, forexample, as previously described. Each of the compositions of the kitmay be provided in liquid form (e.g., in solution, as a liquid-phasepolymer, etc.), or in solid form (e.g., a reversibly cross-linkedpolymer). In certain cases, some of the compositions may beconstitutable or otherwise processable, for example, by the addition ofa suitable solvent, other species, or source of energy (e.g., UVradiation), which may or may not be provided with the kit. Examples ofother compositions or components associated with the invention include,but are not limited to, solvents, surfactants, diluents, salts, buffers,emulsifiers, chelating agents, fillers, antioxidants, binding agents,bulking agents, preservatives, drying agents, antimicrobials, needles,syringes, packaging materials, tubes, bottles, flasks, beakers, dishes,frits, filters, rings, clamps, wraps, patches, containers, tapes,adhesives, and the like, for example, for using, administering,modifying, assembling, storing, packaging, preparing, mixing, diluting,and/or preserving the compositions components for a particular use, forexample, to a sample and/or a subject.

A kit of the invention may, in certain cases, include differentcompositions that can be mixed to form a product. In certainembodiments, the kit may include physically separated chambers to holdthe compositions, and a mechanism that is activated by a user or amachine for discharging the compositions and/or mixing them together. Asa non-limiting example, the kit may include a dual barrel syringe havingfirst and second chambers that contain first and second compositions,wherein the first and second chambers are physically separated, forexample by a wall. In this example, the user may depress the plunger ofthe dual-barrel syringe to eject the first and second compositions fromthe first and second chambers. In certain embodiments, the kit alsoincludes a static mixing nozzle, a dynamic mixing nozzle, an impeller,or a mixing chamber to permit the components to mix prior to or duringdischarge.

A kit of the invention may, in some cases, include instructions in anyform that are provided in connection with the compositions of theinvention in such a manner that one of ordinary skill in the art wouldrecognize that the instructions are to be associated with thecompositions of the invention. For instance, the instructions mayinclude instructions for the use, modification, mixing, diluting,preserving, administering, assembly, storage, packaging, and/orpreparation of the compositions and/or other compositions associatedwith the kit. In some cases, the instructions may also includeinstructions for the delivery and/or administration of the compositions,for example, for a particular use, e.g., to a sample and/or a subject,or to deliver the compositions of the invention into contact with bodilytissues to prevent, limit, or otherwise control bleeding or the flow ofother bodily fluids. The instructions may be provided in any formrecognizable by one of ordinary skill in the art as a suitable vehiclefor containing such instructions, for example, written or published,verbal, audible (e.g., telephonic), digital, optical, visual (e.g.,videotape, DVD, etc.) or electronic communications (including Internetor web-based communications), provided in any manner.

In the compositions of the invention, the term “alkyl” refers tosaturated aliphatic groups, including straight-chain alkyl groups,branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkylsubstituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.In some embodiments, a straight chain or branched chain alkyl may have30 or fewer carbon atoms in its backbone, and, in some cases, 20 orfewer. In some embodiments, a straight chain or branched chain alkyl mayhave 12 or fewer carbon atoms in its backbone (e.g., C₁-C₁₂ for straightchain, C₃-C₁₂ for branched chain), 6 or fewer, or 4 or fewer. Likewise,cycloalkyls may have from 3-10 carbon atoms in their ring structure, or5, 6 or 7 carbons in the ring structure. Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, hexyl,cyclochexyl, and the like.

The term “heteroalkyl” refers to an alkyl group as described herein inwhich one or more carbon atoms is replaced by a heteroatom. Suitableheteroatoms include oxygen, sulfur, nitrogen, phosphorus, and the like.Examples of heteroalkyl groups include, but are not limited to, alkoxy,amino, thioester, and the like.

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double or triple bond respectively.

The terms “heteroalkenyl” and “heteroalkynyl” refer to unsaturatedaliphatic groups analogous in length and possible substitution to theheteroalkyls described above, but that contain at least one double ortriple bond respectively.

As used herein, the term “halogen” or “halide” designates —F, —Cl, —Br,or —I.

The terms “carboxyl group,” “carbonyl group,” and “acyl group” arerecognized in the art and can include such moieties as can berepresented by the general formula:

wherein W is H, OH, O-alkyl, O-alkenyl, or a salt thereof. Where W isO-alkyl, the formula represents an “ester.” Where W is OH, the formularepresents a “carboxylic acid.” The term “carboxylate” refers to ananionic carboxyl group. In general, where the oxygen atom of the aboveformula is replaced by sulfur, the formula represents a “thiolcarbonyl”group. Where W is a S-alkyl, the formula represents a “thiolester.”Where W is SH, the formula represents a “thiolcarboxylic acid.” On theother hand, where W is alkyl, the above formula represents a “ketone”group. Where W is hydrogen, the above formula represents an “aldehyde”group.

The term “aryl” refers to aromatic carbocyclic groups, optionallysubstituted, having a single ring (e.g., phenyl), multiple rings (e.g.,biphenyl), or multiple fused rings in which at least one is aromatic(e.g., 1, 2, 3, 4-tetrahydronaphthyl, naphthyl, anthryl, orphenanthryl). That is, at least one ring may have a conjugated pielectron system, while other, adjoining rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls. The aryl groupmay be optionally substituted, as described herein. “Carbocyclic arylgroups” refer to aryl groups wherein the ring atoms on the aromatic ringare carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclicaryl groups and polycyclic or fused compounds (e.g., two or moreadjacent ring atoms are common to two adjoining rings) such as naphthylgroups. In some cases, the:

The term “alkoxy” refers to the group, —O-alkyl.

The term “aryloxy” refers to the group, —O-aryl.

The term “acyloxy” refers to the group, —O-acyl.

The term “aralkyl” or “arylalkyl”, as used herein, refers to an alkylgroup substituted with an aryl group.

The terms “heteroaryl” refers to aryl groups comprising at least oneheteroatom as a ring atom.

The term “heterocycle” refers to refer to cyclic groups containing atleast one heteroatom as a ring atom, in some cases, 1 to 3 heteroatomsas ring atoms, with the remainder of the ring atoms being carbon atoms.Suitable heteroatoms include oxygen, sulfur, nitrogen, phosphorus, andthe like. In some cases, the heterocycle may be 3- to 10-membered ringstructures or 3- to 7-membered rings, whose ring structures include oneto four heteroatoms. The term “heterocycle” may include heteroarylgroups, saturated heterocycles (e.g., cycloheteroalkyl) groups, orcombinations thereof. The heterocycle may be a saturated molecule, ormay comprise one or more double bonds. In some case, the heterocycle isa nitrogen heterocycle, wherein at least one ring comprises at least onenitrogen ring atom. The heterocycles may be fused to other rings to forma polycylic heterocycle. The heterocycle may also be fused to aspirocyclic group. In some cases, the heterocycle may be attached to acompound via a nitrogen or a carbon atom in the ring.

Heterocycles include, for example, thiophene, benzothiophene,thianthrene, furan, tetrahydrofuran, pyran, isobenzofuran, chromene,xanthene, phenoxathiin, pyrrole, dihydropyrrole, pyrrolidine, imidazole,pyrazole, pyrazine, isothiazole, isoxazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole,phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane,thiolane, oxazole, oxazine, piperidine, homopiperidine(hexamnethyleneimine), piperazine (e.g., N-methyl piperazine),morpholine, lactones, lactams such as azetidinones and pyrrolidinones,sultams, sultones, other saturated and/or unsaturated derivativesthereof, and the like. The heterocyclic ring can be optionallysubstituted at one or more positions with such substituents as describedherein. In some cases, the heterocycle may be bonded to a compound via aheteroatom ring atom (e.g., nitrogen). In some cases, the heterocyclemay be bonded to a compound via a carbon ring atom. In some cases, theheterocycle is pyridine, imidazole, pyrazine, pyrimidine, pyridazine,acridine, acridin-9-amine, bipyridine, naphthyridine, quinoline,benzoquinoline, benzoisoquinoline, phenanthridine-1, 9-diamine, or thelike.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that can berepresented by the 30 general formula: N(R′)(R″)(R′″) wherein R′, R″,and R′″each independently represent a group permitted by the rules ofvalence. An example of a substituted amine is benzylamine.

Any of the above groups may be optionally substituted. As used herein,the term “substituted” is contemplated to include all permissiblesubstituents of organic compounds, “permissible” being in the context ofthe chemical rules of valence known to those of ordinary skill in theart. It will be understood that “substituted” also includes that thesubstitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. In some cases, “substituted” maygenerally refer to replacement of a hydrogen with a substituent asdescribed herein, e.g., a drug or a peptide. However, “substituted,” asused herein, does not encompass replacement and/or alteration of a keyfunctional group by which a molecule is identified, e.g., such that the“substituted” functional group becomes, through substitution, adifferent functional group. For example, a “substituted phenyl group”must still comprise the phenyl moiety and cannot be modified bysubstitution, in this definition, to become, e.g., a pyridine ring. In abroad aspect, the permissible substituents include acyclic and cyclic,branched and unbranched, carbocyclic and heterocyclic, aromatic andnonaromatic substituents of organic compounds. Illustrative substituentsinclude, for example, those described herein. The permissiblesubstituents can be one or more and the same or different forappropriate organic compounds. For purposes of this invention, theheteroatoms such as nitrogen may have hydrogen substituents and/or anypermissible substituents of organic compounds described herein whichsatisfy the valencies of the heteroatoms.

Examples of substituents include, but are not limited to, halogen,azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl,amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate,carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido,ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaruomaticmoieties, —CF3, —CN, aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, halide,alkylthio, oxo, acylalkyl, carboxy esters, -carboxamido, acyloxy,aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl,arylamino, aralkylamino, alkylsulfonyl, -carboxamidoalkylaryl,-carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-,aminocarboxamidoalkyl-, cyano, alkoxyalkyl, perhaloalkyl,arylalkyloxyalkyl, and the like. The peptides described herein areinclusive of at least two amino acids connected by amide bond.

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. Itis, therefore, to be understood that the foregoing embodimentsare presented by way of example only and that, within the scope of theappended claims and equivalents thereto, the invention may be practicedotherwise than as specifically described and claimed. The presentinvention is directed to each individual feature, system, article,material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Other elements may optionallybe present other than the elements specifically identified by the“and/or” clause, whether related or unrelated to those elementsspecifically identified unless clearly indicated to the contrary. Thus,as a non-limiting example, a reference to “A and/or B,” when used inconjunction with open-ended language such as “comprising” can refer, inone embodiment, to A without B (optionally including elements other thanB); in another embodiment, to B without A (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or“exactly one of,” or, when used inthe claims, “consisting of,” will refer to the inclusion of exactly oneelement of a number or list of elements. Ingeneral, the term “or” asused herein shall only be interpreted as indicating exclusivealternatives (i.e. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” and the like are to be understoodto be open-ended, i.e., to mean including but not limited to. Only thetransitional phrases “consisting of” and “consisting essentially of”shall be closed or semi-closed transitional phrases, respectively, asset forth in the United States Patent Office Manual of Patent ExaminingProcedures, Section 2111.03.

1. A system for forming a medical implant to control the flow of bodilyfluids in a patient in need thereof, comprising: a first composition anda second composition, wherein the second composition is physicallyseparated from the first composition; a mechanism that places the firstcomposition into contact with the second composition to form a polymericcomposition, wherein the mechanism is selected from a syringe plunger, astatic mixing nozzle, dynamic mixing nozzle, and an impeller; and anintroducer to be inserted into the body of the patient, wherein theintroducer is configured to permit the flow of the polymeric compositioninto a body cavity of the patient, wherein the polymeric composition,after being inserted into the body cavity, forms a material whichcontrols the flow of bodily fluids in the patient.
 2. The system ofclaim 1, wherein the material is hydrophobic.
 3. The system of claim 1,wherein the material comprises chitosan.
 4. A system for forming amedical implant to control bleeding in a patient in need thereof,comprising: a first composition and a second composition, wherein thesecond composition is physically separated from the first composition; amechanism that places the first composition into contact with the secondcomposition to form a polymeric composition, wherein the mechanism isselected from a syringe plunger, a static mixing nozzle, dynamic mixingnozzle, and an impeller, and an introducer to be inserted into the bodyof the patient, wherein the introducer is configured to permit the flowof polymeric material into a body cavity of the patient, wherein thepolymeric composition, after being inserted into the body cavity, formsa material which controls bleeding in the patient.
 5. The system ofclaim 4, wherein the material is hydrophobic.
 6. The system of claim 4,wherein the material comprises chitosan.
 7. A method of forming amedical implant for controlling the flow of bodily fluids in a patientin need thereof, the method comprising: (a) providing a systemcomprising: a first composition and a second composition, wherein thesecond composition is physically separated from the first composition; amechanism that places the first composition into contact with the secondcomposition to form a polymeric composition, said mechanism selectedfrom a syringe plunger, a static mixing nozzle, dynamic mixing nozzle,and an impeller, and an introducer to be inserted into a body of apatient, wherein the introducer is configured to permit the flow of thepolymeric composition into a body cavity of the patient; and (b)inserting the polymeric material from the system and into the patientvia the introducer, wherein the polymeric composition, after beinginserted into the body cavity, forms a material which controls the flowof bodily fluids in the patient.
 8. The method of claim 7, wherein thematerial is hydrophobic.
 9. The method of claim 7, wherein the materialcomprises chitosan.
 10. A method of forming a medical implant forcontrolling bleeding in a patient in need thereof, the methodcomprising: (a) providing a system comprising: a first composition and asecond composition, wherein the second composition is physicallyseparated from the first composition; a mechanism that places the firstcomposition into contact with the second composition to form a polymericcomposition, said mechanism selected from a syringe plunger, a staticmixing nozzle, dynamic mixing nozzle, and an impeller; and an introducerto be inserted into a body of a patient, wherein the introducer isconfigured to permit the flow of the polymeric composition into a bodycavity of the patient; and (b) inserting the polymeric material from thesystem and into the patient via the introducer, wherein the polymericcomposition, after being inserted into the body cavity, forms a materialwhich controls bleeding in the patient.
 11. The method of claim 10,wherein the material is hydrophobic.
 12. The method of claim 10, whereinthe material comprises chitosan.